Antithyroid Drug Therapy

Medical treatment in the first half of the century consisted of bed rest, quinine, and iodine in the form of Lugol's solution [98]. Partial thyroidectomy was used to provide permanent cures [98]. With the advent of thiouracil and propylthiouracil (PTU) in the mid-1940s, medical therapy of Graves' improved markedly [99]. Because of the relatively high incidence of toxic reactions that developed following the administration of thiouracil including agranulocyto-sis, leukopenia, and drug fever, PTU became the mainstay of medical therapy [99] and was later joined by methimazole (MMI) as an effective treatment option.

PTU and MMI reduce thyroid hormone synthesis by inhibiting the oxidation and organic binding of thyroid iodide [100, 101]. These medications are not curative. Rather, they palliate the hyperthyroid state until it spontaneously resolves or definitive treatment is rendered.

MMI is tenfold more potent than PTU and has a longer half-life [100, 101]. Recommended doses for initial therapy are 5-10mg/kg per day for PTU and 0.5 to 1.0mg/kg per day for MMI [102]. Yet, even lower doses of PTU or MMI may be effective for induction or maintenance therapy.

To control the hyperthyroid state, PTU and MMI are typically given every eight hours. However, once-a-day dosing may bring remission as rapidly as divided doses [102-104] and is well suited for maintenance therapy [105, 106]. Because MMI pills (5 or 10 mg) are smaller than PTU tablets (50 mg), and fewer MMI pills are generally need, MMI may be more convenient.

In contrast to oral iodine therapy (see below), thiouracil drugs do not prevent thyroid gland hyperplasia. Thus, thyroid enlargement may occur during therapy. The thyroid gland may become softer and the outlines of the gland more difficult to distinguish [99]. Because radioactive iodine is less effective in large than in small glands [59, 99, 107], thyroid size should be continuously monitored for progressive thyroid enlargement that may make the patient an unsuitable candidate for radioactive iodine treatment. If the gland enlarges, this may also be due to hypothyroidism. Thus, patients should be monitored for TSH elevations.

Although MMI and PTU promptly inhibit hormone formation, they do not inhibit hormone release. Thus, levels of circulating thyroid hormones may remain elevated for several weeks as stored hormone is released. Until circulating levels of thyroid hormones normalize, the signs and symptoms of hyperthyroidism may be controlled with beta-blockers such as atenolol (25 or 50 mg, QD or BID) or propranolol (2.5-10 mg b.i.d. or t.i.d.). If the child has reactive airway disease, beta-blocker therapy may trigger acute exacerbations of asthma. In this setting we have had success using metoprolol, which is a cardiac-selective beta-blocker.

Thyrotoxicosis can be controlled more quickly than with thionamides using solutions of saturated potassium iodine (SSKI or Lugol's solution; 1-3 drops t.i.d.) which blocks the release of stored hormones. Side effects of iodine are uncommon and include acneiform eruptions, fever, coryza, and salivation [99]. Severe and fatal allergic reactions to iodine have also been observed [99].

When combined thionamide and iodine therapy is used, PTU or MMI should be given a few hours before iodine to prevent iodine-induced increases in thyroid hormone synthesis [99].

After initiation of treatment with PTU or MMI, maximal clinical responses are seen after 4-6 weeks, at which time biochemical hypothyroidism develops. The thionamide dose can then be reduced 30-50%. To achieve a euthyroid state, the dose of MMI or PTU can either be reduced further, or supplementation with L-thyroxine started.

Complications of PTU and MMI

An apparent difference between the adult and pediatric populations is the higher incidence of adverse side effects of antithyroid medications in the young. Published studies including 500 children [6, 13, 59, 108, 109], show that complications of drug therapy include increases in liver enzymes (28%) and leukopenia (25%). Up to 0.5% of propylthiouracil (PTU) or methimazole (MMI)-treated children will develop serious complications [6, 10]. By 1998, 36 serious adverse events and two deaths from liver failure (from PTU) due to antithyroid drug therapy of childhood Graves' disease had been reported to the FDA MedWatch Program, which is very prone to under reporting [6]. In addition, at least five other deaths related to antithyroid medication therapy in children have been reported to me by professionals. Other rare and serious adverse effects of thionamide drugs include periarteritis nodosa, other forms of vasculi-tis, nephrotic syndrome, hypothrombinemia, and aplastic anemia [6].

Most side effects of antithyroid drugs develop within eight weeks of starting therapy. However, adverse effects may develop later. Parents should be instructed to contact their physician promptly if fever, sore throat, oral ulceration, rash, joint pain, nausea, abdominal pain, or any other unusual symptoms develop, and stop medical therapy.

When an adverse event related to either PTU or MMI occurs, some physicians will switch to another thionamide. Published data about the risks of changing to another medication following the occurrence of toxic reactions in children are limited [16]. Thus, faced with major or minor side effects in up to 20% of patients in the midst of a course of drug therapy, physicians will be faced with either electing for definitive therapy or an alternative medication.

Serious side effects of antithyroid drugs often develop within the first few months of therapy onset; however, adverse effects may develop after several years of antithyroid therapy. Increasing reports describe the development of anti-neutrophil-cytoplasmic antibodies (ANCAs) with prolonged medical therapy of Graves' disease [110-112], which are associated with vasculitis. In adults, up to 15% of individuals treated with PTU, develop ANCAs after 2 years of therapy [110, 111]. MMI use is associated with the occurrence of ANCAs, albeit with a lower incidence than PTU [110, 111]. In the pediatric population, ANCA-mediated disease has been observed in patients treated with PTU or MMI [113, 114]. Because these antibodies can trigger serious vasculitis events, elimination of the trigger of ANCA induction, i.e. antithyroid medications, must be considered [115].

Long-Term Efficacy of Antithyroid Drugs

In children, published remission rates after several years of drug therapy are usually less than 25% [13, 59, 67, 95, 116-118]. It has been suggested that after 2 years of treatment remission rates are 25%, that 4 years of drug therapy are needed to achieve 50% remission rates [109], and that 10 years of drug therapy can achieve remission in 75% of children [109]. However, although widely cited, these theoretical projections have not been substantiated. The most extensive long-term study of this issue involving near 200 children with Graves' disease shows that less than 20% of children treated medically achieve remission lasting greater than 2 years [13]. When responses to medical therapy between prepubertal and pubertal children are compared, 1 year remission rates are also less in prepubertal than in pubertal children [15, 16].

The efficacies of antithyroid drugs appear to be inversely related to serum levels of thyroid-stimulating antibodies (TSAb) or thyrotropin receptor antibodies (TRAbs) [119-123]. After several years of antithyroid therapy, remission rates in adults range from 15% in individuals with high levels of TRAb at the time of diagnosis, to 50% in individuals with low pretreatment TRAb levels [119]. In our experience, if remission occurs with medical therapy (about 15% of our patients; n = 30 patients), it is in the setting of patient with a small thyroid gland (<20 g) and low levels of TRAbs (<110% of control).

It has been suggested that long-term remission rates can be predicted by observing responses to short-term (ca. 6 months) antithyroid drug therapy [17, 124, 125]. Short-term therapy appears to work as well as long-term therapy in patients with mild hyperthyroidism and small goiters, but neither short- nor long-term antithyroid drug therapy is likely to lead to a lasting remission in patients with severe thyrotoxicosis and a large goiter [17, 124, 125]. Although most of the evidence supports the efficacy of short term therapy, some investigators have noted higher relapse rates after short-term than long-term treatment [126, 127].

Risks of Cancer after Drug Therapy

Antithyroid drugs are preferred to radioactive iodine therapy by many clinicians based on the assumption that cancer risk is less after drug therapy than after radioactive iodine. However, data do not support that this assumption.

The largest long-term follow-up study of thyroid cancer risks after treatment of Graves' disease by the (CTSG), revealed that the incidence of thyroid carcinomas over 10-20 years of follow-up (not lifetime incidence) is fivefold higher in adults with Graves' disease treated with thionamide drugs (follow-up period normalized incidence rate = 1 case per 332 individuals) than in patients treated with 131I (1/1,783), and eightfold higher than in patients treated surgically (1/2,820) [77]. The incidence of thyroid adenomas are also 10 and 20 times higher among the adults treated with antithyroid drugs (1/76) than in patients treated with 131I (1/802) or surgery (1/1,692), respectively [77]. Rather than reflecting a causative role for medical therapy in the pathogenesis of thyroid neo-plasia, these observations may reflect the persistence of more thyroid tissue in patients treated with drugs than in individuals treated with radioactive iodine or surgery.

Although CTSG data show an increased rate of thyroid cancer in the drug-treated patients [77], it is important to note that thyroid cancer mortality rates were not increased in the CTSG patients treated with drugs [84]. We are also unaware of thyroid cancer cases in the large numbers of children treated with antithyroid drugs alone.

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